Field of the Invention
The present invention relates to the field of biomedical engineering and medical treatment of diseases and disorders. More specifically, embodiments of the invention relate to a device and method for destroying aberrant cells, including tumor tissues, using high-frequency, bipolar electrical pulses having a burst width on the order of microseconds and duration of single polarity on the microsecond to nanosecond scale.
Description of Related Art
Electroporation based therapies typically involve delivering multiple, unipolar pulses with a short duration (˜100 μs) through electrodes inserted directly into, or adjacent to, the target tissue. See Nuccitelli, R., X. Chen, A. G. Pakhomov, W. H. Baldwin, S. Sheikh, J. L. Pomicter, W. Ren, C. Osgood, R. J. Swanson, J. F. Kolb, S. J. Beebe, and K. H. Schoenbach, A new pulsed electric field therapy for melanoma disrupts the tumor's blood supply and causes complete remission without recurrence. Int J Cancer, 2009. 125(2): p. 438-45; Davalos, R. V., L. M. Mir, and B. Rubinsky, Tissue ablation with irreversible electroporation. Ann Biomed Eng, 2005. 33(2): p. 223-31 (“Davalos 2005”); Payselj, N., V. Preat, and D. Miklavcic, A numerical model of skin electroporation as a method to enhance gene transfection in skin. 11th Mediterranean Conference on Medical and Biological Engineering and Computing 2007, Vols 1 and 2, 2007. 16(1-2): p. 597-601 (“Payselj 2007”); and Payselj, N., Z. Bregar, D. Cukjati, D. Batiuskaite, L. M. Mir, and D. Miklavcic, The course of tissue permeabilization studied on a mathematical model of a subcutaneous tumor in small animals. Ieee Transactions on Biomedical Engineering, 2005. 52(8): p. 1373-1381.
The extent of electroporation is attributed to the induced buildup of charge across the plasma membrane, or transmembrane potential (TMP). See Abidor, I. G., V. B. Arakelyan, L. V. Chernomordik, Y. A. Chizmadzhev, V. F. Pastushenko, and M. R. Tarasevich, Electric Breakdown of Bilayer Lipid-Membranes 0.1. Main Experimental Facts and Their Qualitative Discussion . Bioelectrochemistry and Bioenergetics, 1979. 6(1): p. 37-52; Benz, R., F. Beckers, and U. Zimmermann, Reversible electrical breakdown of lipid bilayer membranes: a charge-pulse relaxation study. J Membr Biol, 1979. 48(2): p. 181-204; Neumann, E. and K. Rosenheck, Permeability changes induced by electric impulses in vesicular membranes. J Membr Biol, 1972. 10(3): p. 279-90; Teissie, J. and T. Y. Tsong, Electric-Field Induced Transient Pores in Phospholipid-Bilayer Vesicles . Biochemistry, 1981. 20(6): p. 1548-1554; Zimmermann, U., G. Pilwat, and F. Riemann, Dielectric breakdown of cell membranes . Biophys J, 1974. 14(11): p. 881-99; and Kinosita, K. and T. Y. Tsong, Formation and Resealing of Pores of Controlled Sizes in Human Erythrocyte-Membrane . Nature, 1977. 268(5619): p. 438-441.
Once the TMP reaches a critical voltage, it is thought that permeabilizing defects, or pores, form in the plasma membrane in attempt to limit further TMP rise. Pore formation can either be reversible to allow for the introduction of foreign particles into viable cells, or irreversible to promote cell death through a loss of homeostasis. Known devices and methods of performing electroporation clinically involve several drawbacks, including painful muscle contractions, unpredictable treatment outcomes, and a high potential for thermal damage in low passive conductivity tissues.
IRE performed with unipolar pulses causes intense muscle contractions. Therefore, clinical applications of IRE require the administration of general anesthesia and neuroparalytic agents in order to eliminate the discomfort caused by muscle contractions seen during each pulse. See Talele, S. and P. Gaynor, Non-linear time domain model of electropermeabilization: Response of a single cell to an arbitrary applied electric field. Journal of Electrostatics, 2007. 65(12): p. 775-784. Receiving paralytic agents is undesirable for patients, and may deter them from seeking an electroporation based therapy. Further, in some cases, even with an adequate neuromuscular blockade, muscle contractions are still visible (see Payselj 2007), and questions remain as to what constitutes an appropriate dosage. Muscle contractions may affect the location of implanted needle electrodes, which can invalidate treatment planning algorithms Additionally, in treatments near vital structures, displacement of the implanted electrodes may cause unavoidable collateral damage.
The time course of the pulsed electric field and dielectric properties of the tissue control the TMP development and the extent to which the transient defects form and reseal within the membrane. Knowledge of these two components can be used to predict treatment outcomes. However, predictions are complicated in heterogeneous tissues, or organs with multiple types of parenchymal tissue. There is often an intricate and unknown geometrical arrangement between tissues of low and high electrical conductivity, and the conductivity can change in real-time due to the phenomenon of electroporation, the extent of which is highly unpredictable without prior knowledge.
Low conductivity tissues, such as epithelial layers, often contain a dense packing of cells with reduced extracellular current pathways. As such, the resistance of the extracellular space is increased. Additionally, when pulses much longer than the charging time of the plasma membrane (˜1 μs) are applied (see T. R., A. T. Esser, Z. Vasilkoski, K. C. Smith, and J. C. Weaver, Microdosimetry for conventional and supra-electroporation in cells with organelles. Biochem Biophys Res Commun, 2006. 341(4): p. 1266-76, “Gowrishankar 2006”), the current is confined to the extracellular space prior to the onset of electroporation, as shown in FIGS. 1A-B. As shown, when the pulse duration (td) is much less than the plasma membrane time constant (τpm), current flows through both intracellular and extracellular spaces (FIG. 1A). In the case that td is much greater than τpm, current flow is restricted to the narrower extracellular spaces (FIG. 1B). Consequently, there is a large voltage drop across tissues with low conductivity, which increases the potential for deleterious Joule heating effects, such as thermal damage.